Electrolytic deuteration of unsaturated bonds without using D2

Abstract

Site-selective deuteration of C–H bonds increases the lifetime and efficacy of drug molecules. Although effective methods to form C(sp2)–D bonds are known, processes for making C(sp3)–D bonds often have low site selectivity, require expensive and unrecoverable D2 gas, or use stoichiometric reagents. Here we report cost-efficient and site-selective reductive deuteration using a tandem electrochemical chemical palladium membrane reactor. This architecture mediates the chemical reaction of deuterium atoms (derived from reusable D2O in an electrochemical compartment) with alkynes, aldehydes and imines. The formation of C(sp3)–D and C(sp2)–D bonds in the isolated chemical compartment is made possible by the deuterium-selective permeability of the membrane that partitions the electrochemical compartment from the chemical compartment. We have utilized the reactor for the deuteration step in the construction of a common drug, cinacalcet, to demonstrate that this method can be used to incorporate deuterium atoms in a pharmaceutical. The reductive deuteration of unsaturated hydrocarbons is a promising deuterium-labelling strategy, although it requires expensive gaseous D2 or other stoichiometric reagents. Here, an electrocatalytic palladium membrane reactor is employed to selectively generate C(sp3)–D bonds via reduction of unsaturated compounds using D2O.